We report an open evaluation of ofloxacin therapy, 400 mg every twelve hours (parenterally followed by oral treatment) in hospitalized subjects with infections of the skin and skin structure that were recalcitrant. There were 105 evaluable subjects with an average age of fifty-five years, thirty-two (30 percent) of whom had diabetes mellitus, and in sixty-one (58 percent), a regimen of parenteral antibiotics (typically combinations involving aminoglycosides) had recently failed. There were 115 pathogens isolated; the most common were Enterobacteriaceae (fifty-five), Staphylococcus aureus (thirty), coagulase-negative Staphylococcus (ten), and Pseudomonas aeruginosa (ten). Overall, 103 (90 percent) pathogens were eradicated by therapy, and twelve (10 percent) persisted, including four coagulase-negative Staphylococcus which emerged as resistant during therapy. For thirty-five (33 percent) subjects, colonization or superinfection was documented; seven of these organisms (five Enterococcus, one S. aureus, and one P. aeruginosa) were resistant to treatment with ofloxacin. Clinical response was rated as cure in seventy (67 percent) subjects, improvement in twenty-one (20 percent) subjects, and failure in fourteen (13 percent). Failures were accompanied by persistence of the original pathogen (eight), persistent or resistant superinfection (six), or both (one). Adverse effects were infrequent, mild, and self-limiting. There was one death during the study, attributed to septic shock after postoperative abdominal leak, and not related to ofloxacin therapy. Intravenous/oral ofloxacin is effective and safe for the treatment of many difficult infections of the skin and skin structure, including those in diabetic subjects and in patients in whom previous parenteral therapy may have failed.